Notes

Aimed towards most cancers come tissues through integrin β4.
Third, to identify NO-regulated Cys oxidation using mass spectrometry, we compared the redox status of all Cys identified in tryptic peptides, among which, ten were oxidized and two were reduced in NO-stimulated GC1. Fourth, we resorted to computational modeling to narrow down the Cys candidates potentially involved in disulfide bond and identified Cys489 and Cys571. Fifth, our mutational studies showed that Cys489 and Cys571 were involved in GC1'response to NO, potentially as a thiol/disulfide switch. These findings imply that specific GC1 Cys sensitivity to redox environment is critical for NO signaling in cardiovascular physiology.Paracetamol printlets were prepared via hot-melt extrusion process and fused deposition modelling, using two types of backbone polymers. Deferiprone Polycaprolactone (PCL) and Polyethylene oxides (PEO) 100 K and 200 K were used, while Arabic gum was used as a plasticizer to facilitate the material flow and Gelucire® 44/14 as an enhancer of drug release. Different drug/polymer ratios were prepared. Extrusion temperature was adjusted according to the mixture/polymer types. It was possible to produce filaments with maximum of 60% w/w of drug. Mechanical properties of filaments were evaluated using three-point bend test, while obtained parameters were modelled using decision tree as a data mining method. Correlation between maximum displacement, maximum force and printability was obtained with accuracy of 84.85% and can be a useful tool for predicting printability of filaments. This study briefly demonstrated that backbone polymer in formulation plays crucial role in obtaining FDM printlets with desired properties. PEO-based filaments were more prone to be clogged in printcore, but their printlets showed much faster drug release. Drug release from all printlets was prolonged from 50% in 8 h (PCL), to complete release in 4 h (PEO). Paracetamol release kinetics was guided by anomalous transport, attributed to the diffusion and erosion process.Inhalation drug delivery has seen a swift rise in the use of dry powder inhalers (DPIs) to treat chronic respiratory conditions. However, universal adoption of DPIs has been restrained due to their low efficiencies and significant drug losses in the mouth-throat region. Aerosol efficiency of DPIs is closely related to the fluid-dynamics characteristics of the inhalation flow generated from the devices, which in turn are influenced by the device design. In-vitro and particle image velocimetry (PIV) have been used in this study to assess the aerosol performance of a model carrier formulation delivered by DPI devices and to investigate their flow characteristics. Four DPI device models, with modification to their tangential inlets and addition of a grid, have been explored. Similar aerosol performances were observed for all four device models, with FPF larger than 50%, indicating desirable lung deposition. A high swirling and recirculating jet-flow emerging from the mouthpiece of the DPI models without the grid was observed, which contributed to particle deposition in the throat. DPI models where the grid was present showed a straightened outflow without undesired lateral spreading, that reduced particle deposition in the throat and mass retention in the device. These findings demonstrate that PIV measurements strengthen in-vitro evaluation and can be jointly used to develop high-performance DPIs.An understanding of the factors that affect liposome size, drug loading, stability and drug release is critical for the rational design of liposomes with desired pharmacokinetics and biodistribution. This article presents a report on the formulation and characterization of BIIB093 (glibenclamide) liposomes as well as a detailed analysis of the influence of formulation methods and parameters on encapsulation efficiency, liposome size, charge (zeta potential, ZP), polydispersity index (PDI), and drug release. PEGylated liposomes containing BIIB093 were made using ethanol injection and calcium acetate remote loading. The critical formulation parameters investigated include the effect of lipid chain length, lipid unsaturation, lipid phase transition temperature (Tc) and the amount of cholesterol. Liposomes generated in this study had low average particle size (130 ± 20 nm), PDI (0.15 ± 0.1) and ZP (-2 ± 1 mV). Liposomes made from lipids with long acyl chains showed enhanced drug loading, encapsulation efficiency and drug retention. Similarly, liposomes made from lipids with high degree of unsaturation and low Tc exhibited faster drug release rates. Additionally, increasing the amount of cholesterol in the liposome bilayer improved PDI, decreased drug incorporation and accelerated drug release but had negligible impact on liposome size and ZP. Furthermore, encapsulating the drug in the liposome core enabled sustained drug release.Multiple signaling pathways are usually involved in the development of tumors. Compared with monospecific antibodies, bispecific antibodies can recognize two different antigens at the same time, so they are more suitable for treating tumor diseases with complex etiology. Immunotoxins have good antitumor activity, however, single targeting limits their effectiveness. Herein, we designed a Pseudomonas exotoxin A (PE)-based bispecific immunotoxin IgBD-HER2-PDGFRβ-PE38 which could distinguish HER2 and PDGFRβ target in tumor. Meanwhile, IgG-affinity could extend the serum retention of immunotoxins after in vivo injection. In this work, we first detected the selective binding of the immunotoxins and antitumor effect in vitro. Compared with control group, IgBD-HER2-PDGFRβ-PE38 exhibited improved efficacy against HER2-positive tumors in an NCI-N87 subcutaneous xenograft model. Then, transcriptome sequencing was performed on tumor tissue originating from different treatment groups of mice bearing NCI-N87 tumors. Seven significantly differentially expressed genes were screened based on human genes, and the differential mouse genes were enriched based on the Reactome Pathway Database. At last, the RNA sequencing results were verified by real-time PCR and ELISA. Therefore, the new construct bispecific immunotoxin represents a potentially attractive therapeutic modality, and the proposed strategy make them promising for use in the development of anti-HER2 cancer therapeutics.The presence of a 'significant dead zone' in any continuous manufacturing equipment may affect the product quality and need to be investigated systematically. Dead zone will affect the residence time distribution (RTD) of continuous manufacturing and thus the mixing and product quality. Tablet press (feed frame) is one of unit operations that directly influence the critical quality attributes (CQA's). However, currently no systematic methods and tools are available to characterize and model the feed frame dead zone. In this manuscript, the RTD of the tablet press feed frame containing dead zone is investigated. Step-change experiments revealed that the feed frame could be expressed as a traditional continuous stirred tank model. The volume fractions of the dead zones are determined experimentally as well as using RTD model. In addition, an in-line NIR method for drug concentration monitoring inside the feed frame is also developed. The developed NIR calibration model enables to monitor the drug concentration precisely and detect the variation immediately with the probe positioned right above the left paddle. It is also found that the feed frame paddle speed slightly affects the predictive accuracy of NIR, while the die disc speed has no significant effect.The objective of the present study was to evaluate discomfort and safety of microneedle (MN) insertion in several intraoral regions. A device was developed to standardize MN insertions. MNs were inserted in the following regions of the oral cavity gingiva, palatine alveolar process, buccal mucosa, dorsum of the tongue and inner portion of the lower lip. Perforations from MNs post insertion were confirmed with topical gentian violet stain. Pain was evaluated in a randomized, double-blinded, crossover study in 30 volunteers. Each volunteer received a MN patch, a 30G hypodermic needle (positive control) and an identical MN patch with its needles laying flat in the plane of the patch (negative control). Adverse events were visually evaluated immediately after (0 h) and 24 h post MN application. The application device developed a consistent application force (10 N) and promoted perforation of all individual MNs on a patch. At all sites, insertion of the hypodermic needle promoted more pain when compared to the negative control (p 0.05). Hypodermic needle caused bleeding at all insertion sites. In contrast, MNs did not cause bleeding at most sites except in some cases of insertion into the hard gingiva and the palatine alveolar process where tiny blood spots appeared immediately after MN application for few of the MNs on the patch. There were no cases of bleeding at 24 h post MN application. In conclusion, MNs can perforate different sites of the oral cavity in a safe and significantly less painful manner as compared to the 30G hypodermic needle. Thus, analogous to the skin, MN-based approaches could be an attractive approach for drug delivery in the oral cavity.Currently, there is a need for new technology for in-line or fast at-line assessment of solid material porosity. One specific gap is a fast technology to be used in connection to roller compaction (RC) manufacturing, where the porosity of the RC ribbons is critical to the manufacturing of tablets of the right tensile strength and disintegration properties. In this paper, the development of an at-line technology for fast, non-destructive assessment of porosity of RC ribbons is reported. The technology is based on a diode laser spectroscopic technique called Gas in scattering media absorption spectroscopy (GASMAS). GASMAS measures the sample voids by laser light, giving the distance through air. The total distance the light travels is measured using time-of-flight spectroscopy (TOFS). The ratio of these measures gives an "optical porosity", which through theory relates to the porosity of the sample. We present a description of the technology, evaluations of measurement robustness and results from an experimental design where roller compactor, roll force, roll gap and formulation were varied. It is concluded that the data from two different pharmaceutical formulations is supported by the same calibration curve, which indicates that optical porosimetry is a general technique for pharmaceutical materials that does not require frequent calibrations.The nucleus accumbens (NAc) is critical for regulating the appetitive and consummatory phases of motivated behavior. These experiments examined the effects of dopamine and opioid receptor manipulations within the NAc during an effort-based choice task that allowed for simultaneous assessment of both phases of motivation. Male Sprague-Dawley rats received bilateral guide cannulas targeting the NAc core and were tested in 1-hr sessions with free access to rat chow and the choice to work for sugar pellets on a progressive ratio 2 (PR2) reinforcement schedule. Individual groups of rats were tested following stimulation or blockade of NAc D1-like or D2-like receptors, stimulation of μ-, δ-, or κ-opioid receptors, or antagonism of opioid receptors. Behavior was examined under ad libitum conditions and following 23-h food restriction. NAc blockade of the D1-like receptors or stimulation of the D2 receptor reduced break point for earning sugar pellets; D2 receptor stimulation also modestly lowered chow intake. NAc μ-opioid receptor stimulation increased intake of the freely-available chow while simultaneously reducing break point for the sugar pellets.
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